The modulation of necroptosis and its therapeutic potentials

Abstract

Necroptosis is a form of cell death regulated by specific cellular protein machinery. Although the cell death is tightly controlled like apoptosis, another type of programed cell death, the biological features of necroptosis rather resemble necrosis that is defined as an uncontrolled accidental cell death. The pathway executing necroptosis relies on a protein kinase, RIPK3, and its downstream effector molecule, MLKL. Upon necroptosis initiating signals, both RIPK3 and MLKL undergo extensive post-translation modifications to construct a death complex called necrosome, finally leading to lysis of cell membrane. Preclinical mouse models demonstrated the physiological importance of necroptosis in the progress of various inflammation-associated diseases. The objective of this brief review is to introduce a new emerging concept in cell death biology and to provide a first entry into the research field of necroptosis. The uncovering of necroptosis pathway brought a fundamental change in the basic concept that necrotic cell death is passive and unregulated. Currently, multiple small molecules that can target necrotic cell death are under development and some of them are under clinical trials to evaluate their therapeutic potentials. Better understanding of the molecular mechanism leveraging necroptosis will provide an unprecedented opportunity to pathological necrosis-driven human diseases.